对羟苯基丙酮酸双加氧酶（HPPD）是当前除草剂开发的重要靶标之一。由于部分商品化除草剂在不同种属HPPD之间的选择性差，给环境生态造成了一定风险。因此，如何提高种属选择性是靶向HPPD创制新型除草剂时必须要解决的关键科学问题。现有HPPD抑制剂均为底物竞争性抑制剂，由于不同种属HPPD活性腔的结构高度保守，因此底物竞争性抑制剂要想产生理想的选择性难度很大。相反，变构位点由于具有多样化，使得变构抑制剂更容易产生理想的选择性。因此，本项目拟围绕“高种属选择性HPPD变构抑制剂设计”，综合利用结构生物学、化学生物学、有机合成及高性能计算模拟等多学科前沿技术，开展多种属HPPD的比较化学生物学研究，揭示种属选择性的分子机制；预测变构位点，并基于不同种属HPPD的结构特征来设计合成变构抑制剂，通过系统的结构优化获得1~2个具有除草活性的HPPD变构抑制剂先导化合物，为我国新农药创制基础研究贡献力量。

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is one of the most important targets for herbicide discovery. The low species selectivity of some commercial HPPD herbicides leads to some risks to the environment. Thus, improving species selectivity is a key issue that should be dealt with when developing new HPPD inhibitors. The existing HPPD inhibitors are all substrate competitive inhibitors and the structure of substrate binding cavity is highly conserved. It’s hard to obtain substrate competitive inhibitors with high selectivity. In contrast, allosteric site is more diversified and makes inhibitors targeting it have better selectivity. Thus, this project plans to focus on how to design HPPD allosteric inhibitors with high selectivity and comprehensively takes advantage of cutting-edge tools of structural biology, chemical biology, synthetic chemistry and high-performance computing simulations to study biochemical properties of HPPD from different species and reveal the molecular mechanism of selectivity. This project also plans to predict allosteric sites of HPPD and then design and synthesize allosteric inhibitors on the basis of HPPD structures from different species. After comprehensive structure optimization, 1-2 lead compounds which are allosteric inhibitors and have herbicidal activity should be obtained and they can contribute to the basic research on the creation of new pesticides in China.